John A. Bates

Effects of clozapine on auditory event-related potentials in schizophrenia

BACKGROUND Schizophrenia is associated with cognitive deficits that are an intrinsic component of the disorder. Clozapine is an atypical antipsychotic that is superior to typical agents in the treatment of positive symptoms. The degree to which clozapine ameliorates cognitive deficits, however, is still controversial. Mismatch negativity (MMN), N200 (N2), and P300 (P3) are cognitive event-related potentials (ERPs) that index preattentive (MMN) and attention-dependent information processing (N2, P3) and provide a measure of cognitive deficits associated with schizophrenia. In schizophrenic patients deficient generation of MMN, N2, and P3 has been observed, suggesting impairments of discrete stages of information processing. METHODS This study investigates the effects of clozapine treatment on MMN, N2, and P3 generation. Patients were recruited from a haloperidol-controlled, double-blind treatment study of clozapine in chronic schizophrenia. ERPs were obtained at the beginning of the study and after 9 weeks (4 patients) and 16 weeks (13 patients) of treatment. RESULTS Clozapine treatment was associated with a significant increase of P3 amplitude, which was not observed in the haloperidol group; however, clozapine treatment did not affect deficits in MMN and N2. CONCLUSIONS These findings suggest that clozapine--in contrast to conventional antipsychotics--improves electrophysiological measures of attention-dependent information processing, but does not ameliorate preattentive deficits.

Electrophysiological Indices of Automatic and Controlled Auditory Information Processing in First-Episode, Recent-Onset and Chronic Schizophrenia

BACKGROUND Deficits in amplitudes of auditory event-related potentials (ERP) indexing preattentive, automatic (mismatch negativity, MMN) and controlled, attention-dependent (N2, P3) auditory information processing have been well described in chronic schizophrenia. Normal MMN, but deficient N2 and P3 have been reported in first-episode patients. No study has investigated these ERPs concurrently in first-episode patients; thus, reported differences in MMN, N2 and P3 generation may reflect differences in patient samples rather than genuine differences in abnormal generation of these ERPs. METHODS We recorded MMN, N2 and P3 in 26 first-episode patients, 25 recent-onset patients within 1.5 to 5 years after first admission, 25 chronic patients and 39 healthy controls. RESULTS Recent-onset and chronic, but not first-episode patients showed reduced MMN. However, among first-episode patients those with low premorbid educational achievement demonstrated significantly reduced MMN. All patient groups showed pronounced N2 deficits and, to a variable extent, abnormalities in P3 generation. CONCLUSIONS Abnormalities in N2 and P3 generation appear to reflect premorbid neuropathology, whereas MMN deficits may index both ongoing disease processes associated with illness progression as well as premorbid neurocognitive impairment. ERPs may provide tools to assess static and progressive neuropathology in schizophrenia. These findings need confirmation in longitudinal studies.

DTNBP1 genotype influences cognitive decline in schizophrenia.

OBJECTIVE Intellectual decline is common in schizophrenia and predicts functional outcome. While many patients undergo intellectual decline that typically predates the onset of symptoms, few studies have investigated the underlying mechanism through which this occurs. The current study assessed the relationship between intellectual decline in schizophrenia and genetic variation in dysbindin-1 (DTNBP1). METHODS We assessed cognitive decline in 183 Caucasian patients with schizophrenia using a proxy measure of premorbid IQ with which current general cognitive ability (g) was compared. We then tested for a relationship between the risk haplotype identified in previous work (CTCTAC) and intellectual decline. RESULTS We found that carriers of the CTCTAC haplotype, demonstrated a significantly greater decline in IQ as compared with non-carriers (p=0.05). CONCLUSIONS These data suggest that DTNBP1 influences the severity of intellectual decline in schizophrenia and may represent one underlying cause for heterogeneity in cognitive course.

Effects of risperidone on auditory event-related potentials in schizophrenia

Schizophrenia is associated with cognitive deficits for which treatments remain elusive. The effects of risperidone (an antipsychotic differing in some of its pharmacological properties from typical agents) on cognitive deficits have not been extensively investigated. Mismatch negativity (MMN), N2 and P3 are cognitive event-related potentials that index preattentive (MMN) and attention-dependent information processing (N2, P3) and provide a measure of cognitive deficits in schizophrenia. The effects of risperidone treatment on MMN, N2 and P3 generation in chronic schizophrenic patients were investigated in an open- label, uncontrolled study. Risperidone treatment significantly reduced psychotic symptoms. It was associated with a decrease of peak latencies, particularly pronounced for P3. However, it did not significantly affect abnormal MMNor P3 amplitudes. The results suggest an effect of risperidone on processing speed, particularly in attention-dependent tasks. These results are in agreement with findings in recent studies on the cognitive effects of risperidone.

Sex differences in frontal lobe white matter microstructure: a DTI study.

There is evidence that the brains of men and women are structurally different, but there are few data regarding possible sex differences in white matter microstructure. Using diffusion tensor imaging we assessed fractional anisotropy (FA) in the frontal lobe white matter on contiguous 5 mm slices in nine healthy male and 11 healthy female adults. Overall, women had higher FA in the left frontal lobe compared to men and a leftward asymmetry of FA in contrast to men, who showed no hemispheric asymmetry. Among women, greater leftward asymmetry of frontal lobe FA correlated significantly with better verbal comprehension and memory functioning. Our findings may be indicative of increased directional coherence and/or density of left hemisphere white matter fibers and a leftward asymmetry of this structural integrity among women compared to men.

Investigation of unirhinal olfactory identification in antipsychotic-free patients experiencing a first-episode schizophrenia

Although olfactory deficits have been reported in patients with schizophrenia, few studies have examined whether these deficits are lateralized or investigated their possible clinical correlates. In this study, we administered the University of Pennsylvania Smell Identification Test (UPSIT) unirhinally (one nostril at a time) to 15 patients experiencing a first-episode of schizophrenia and 17 healthy comparison subjects. Clinical and olfactory assessments were conducted on the same day in patients while they were antipsychotic drug-free. Patients performed more poorly compared to healthy volunteers in their ability to identify odors across both nostrils, but there were no group differences in right and left nostril impairment. Among patients, greater deficits in grooming and hygiene correlated significantly and more strongly with poorer ability in identifying odors presented to the left compared to the right nostril. Our findings suggest that deficits in grooming and hygiene, including poor body odor, observed in patients experiencing a first-episode of schizophrenia are associated with an impairment in left nostril, and possibly left hemisphere, olfactory processing.

Evidence for impaired visual prediction error in schizophrenia

BACKGROUND Mismatch negativity (MMN) is regarded a prediction error signal that is deficient in schizophrenia in the auditory modality. If, however, MMN reflects a general computational signal of the cortex, then MMN should be also deficient in the visual modality in schizophrenia patients. METHODS Twenty-two schizophrenia patients and 24 matched healthy controls finished a visual oddball task while high-density electroencephalogram was recorded. Visual mismatch negativity was computed as a surrogate marker of prediction error. RESULTS Visual MMN, as measured over posterior extra-striate cortical areas, was significantly reduced in schizophrenia at about 300 ms post stimulus. Standardized mean difference was -.98, corresponding to a large effect size. CONCLUSIONS A posterior visual MMN deficit in schizophrenia is demonstrated for the first time. Our results tentatively suggest a supra-modal MMN deficit in schizophrenia and thus argue in favor of reduced prediction error estimation in schizophrenia.

Acute dopamine depletion with branched chain amino acids decreases auditory top-down event-related potentials in healthy subjects

Cerebral dopamine homeostasis has been implicated in a wide range of cognitive processes and is of great pathophysiological importance in schizophrenia. A novel approach to study cognitive effects of dopamine is to deplete its cerebral levels with branched chain amino acids (BCAAs) that acutely lower dopamine precursor amino acid availability. Here, we studied the effects of acute dopamine depletion on early and late attentive cortical processing. Auditory event-related potential (ERP) components N2 and P3 were investigated using high-density electroencephalography in 22 healthy male subjects after receiving BCAAs or placebo in a randomized, double-blind, placebo-controlled crossover design. Total free serum prolactin was also determined as a surrogate marker of cerebral dopamine depletion. Acute dopamine depletion increased free plasma prolactin and significantly reduced prefrontal ERP components N2 and P3. Subcomponent analysis of N2 revealed a significant attenuation of early attentive N2b over prefrontal scalp sites. As a proof of concept, these results strongly suggest that BCAAs are acting on basic information processing. Dopaminergic neurotransmission seems to be involved in auditory top-down processing as indexed by prefrontal N2 and P3 reductions during dopamine depletion. In healthy subjects, intact early cortical top-down processing can be acutely dysregulated by ingestion of BCAAs. We discuss the potential impact of these findings on schizophrenia research.

Genetic Factors and Neurocognitive Traits

Genetic contributions to phenotypic variation in general intelligence have been studied extensively. Less research has been conducted on genetic contributions to specific cognitive abilities, such as attention, memory, working memory, language, and motor functions. However, the existing data indicate a significant role of genetic factors in these abilities. Stages of information processing, such as sensory gating, early sensory registration, and cognitive analysis, also show evidence of genetic contributions. Recent molecular studies have begun to identify candidate genes for specific cognitive functions. Future research, identifying endophenotypes based on cognitive profiles of neuropsychiatric disorders, may also assist in the detection of genes that increase susceptibility to major psychiatric disorders.

Response to letter to the editor from Schulze et al.—“Is there a phenotypic difference between probands in case-control versus family-based association studies?”

We appreciate the careful review and comments on our Brief Research Communication by Schulze et al. Schulze et al. [2001] are concerned that our results, suggestinga lackofphenotypicdifferencesbetweenschizophrenia probands in case-control association studies (CCPs) versus probands recruited from family-based studies (FBPs), are inconsistent with their own study in bipolar disorder. We would like to take this opportunity to address each of their concerns. Schulze et al. contend that they sufficiently controlled for differences in age at interview, and potential ethnic stratification,with a logistic regression analysis and use of an ethnically homogeneous sample, respectively. Their logistic regression analysis, however, utilized ‘‘suicidality’’ as an outcome measure and did not assess age of onset as an outcome. This is important given the 16-year age difference (47 vs. 31 years) between the two groups included in their study. Moreover, while their efforts to ‘control’ for variables that might confound analysis is laudable, this is difficult when groups differ widely, particularly if there is not compelling evidence of similar relations between regressors and the outcome measures within each group, and is no substitute for experimental control of these variables. Schulze et al. further indicate that their sample was of German descent and thus ethnically homogeneous. It is, however, difficult to rule out ethnic stratification in any Westernpopulation, and this population clearly doesnot represent a genetic isolate. Perhaps Schulze et al. could consider the utilization of genomic control techniques [Pritchard and Rosenberg, 1999] to empirically assess the extent of stratification thatmay exist in their sample as it grows larger. Although our study is the largest examining phenotypic differences between CCPs and FBPs in schizophrenia conducted to date, Schulze et al. note that on one measure in our study the calculated power was 67%. We agree that power is an important consideration and that larger samples are preferable, however, the matched pairs design that we utilized inevitably results in smaller samples. Nevertheless, for the majority of our analyses, our power still remained at or above the 0.80 level. Schulze et al. note that the CVLT and age at onset data resulted in P values between 0.05 and 0.10 and state that these ‘‘might become significant if a few more individuals were included.’’ We are reluctant to over-emphasize ‘‘trend’’ level results because the ‘‘trend’’ may be in either direction. Moreover, the testwise0.05alpha level thatweutilized couldbe considered non-conservative since we conducted eight separate analyses, without correction for multiple comparisons, to minimize the possibility of Type II error. It may be useful in viewing our results to consider the fact that none of eight tests yielded a result with an individual P< 0.05. Finally, Schulze et al. state that age at onset is not a normally distributed variable and thus the t-test may be inappropriate. We are unsure about the validity of this claim; in our data set of 94 schizophrenia cases in their first episode of illness [Bilder et al., 2000]we do not observe significant deviations fromnormality, and the ttest is robust to moderate departures from normality. Moreover, we note that Schulze et al. also utilized a ttest in their analysis of age at onset, we assume because this variablewas seen to benormally distributed in their sample as well. Lastly, Schulze et al. are concerned about diagnostic heterogeneity within our group and request that additional phenotypic characteristics be included in analyses of this sort. We certainly agree that additional phenotypic indices arewelcome, butwe remain cautious about utilizing non-validated, primarily self-report, variables such as ‘‘suicidality’’ or DSM-IV diagnostic subtypes that are known to have limited longitudinal stability and external validity within schizophrenia.We would argue that it is more valuable to seek phenotypes that are more likely relevant to underlying biological proceses and genotypes, among which neurocognitive measures hold great promise. *Correspondence to: Anil K. Malhotra, M.D., Associate Director, Psychiatry Research, The Zucker Hillside Hospital, 75-59 263rd Street, Glen Oaks, NY 11004. E-mail: malhotra@LIJ.edu